Genomics of Intracerebral Hemorrhage and its Causes

脑出血的基因组学及其病因

• 批准号: 10322409
• 负责人: Bradley Pearce Ander
• 金额: $ 58.5万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322409
• 关键词: 3-Dimensional; Accounting; Adverse effects; Affect; Alternative Splicing; Amyloid; Anti-Inflammatory Agents; Attenuated; Blood; Blood - brain barrier anatomy; Blood Coagulation Disorders; Blood Platelets; Blood coagulation; Boston; Brain; Brain hemorrhage; CD14 gene; CD4 Positive T Lymphocytes; Cells; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Classification; Coagulation Process; Data; Dendritic Cells; Down-Regulation; Edema; Excision; Experimental Models; Extravasation; Fibroblast Growth Factor; Gene Expression; Genes; Genomics; Helper-Inducer T-Lymphocyte; Hematoma; Hemorrhage; Hour; Human; Hypertension; Hypertensive Intracerebral Hemorrhage; Immune; Immune response; Incidence; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Interleukin-10; Ischemic Stroke; Lesion; Leukocytes; Lobar; Lymphocyte; MMP9 gene; Measures; Messenger RNA; Microglia; Modeling; Molecular; Molecular Target; Mus; Outcome; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Population; RNA; Recurrence; Regulatory T-Lymphocyte; Resolution; Role; Severities; T cell regulation; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tissues; Transcript; Untranslated RNA; axon injury; base; brain repair; gene repair; hypertensive; improved; improved outcome; insight; ischemic lesion; macrophage; monocyte; mortality; neutrophil; peripheral blood; repaired; response; stroke patient; transcriptome sequencing; γδ T cells

Abstract Following Intracerebral Hemorrhage (ICH), the blood–brain barrier (BBB) is disrupted with associated edema and leukocyte extravasation from blood into the tissue/hematoma. Neutrophils, monocytes and lymphocytes enter brain. Increased neutrophils or increased neutrophil to lymphocyte ratio in humans are associated with worse ICH outcomes. Thus this proposal will examine gene expression in neutrophils, monocytes and T lymphocytes following ICH as compared to ischemic stroke and controls. ICH mortality is very high, with ICH volumes and edema volumes and causes of ICH being important factors in survival. Thus, this proposal will examine gene expression in neutrophils, monocytes and T lymphocytes as function of ICH volume, edema volume and ischemic lesion volume around ICH, as well as causes of ICH. We expect different blood/ leukocyte/ platelet profiles for different ICH volumes and different ICH causes that affect hematoma resolution, recurrent bleeding, and severity of recurrent bleeding that would be molecular targets for improving survival. Based upon very robust preliminary data we propose the following aims. Aim #1a. Demonstrate that proinflammatory genes are expressed at early times (12h, 1d, 3d) in neutrophils, M1 monocytes and specific T cell subsets (γδT cells) following ICH; and immune-related repair genes in M2 monocytes and specific T cell subsets (e.g. T helper cells) are expressed at later times following ICH (3d, 7d); and, show the genes and pathways differ from those for ischemic stroke. Aim #1b. Demonstrate specific T cell, and T-cell receptor gene expression decreases in blood following ICH and this may correlate with decreased numbers of blood T lymphocytes (γδT early; T helper, Tregs later). Aim #2. Determine the genes and pathways that correlate with volume of ICH, edema and ischemic lesions around ICH over time, after accounting for differences in treatment for different sized ICH. Aim #3a. Identify specific genes and pathways associated with deep ICH related to hypertension compared to cortical lobar ICH related to probable CAA as defined by the modified Boston Criteria 23-25. Aim #3b. Demonstrate that, though there are some common genes and pathways associated with all causes of ICH, there are large numbers of genes and pathways that are specific for each cause. The molecular underpinnings underlying human ICH are largely unexplored. Thus, this proposal will begin to increase our understanding of human ICH by identifying molecules that correlate with factors associated with ICH outcomes (neutrophils, monocytes, T lymphocytes, as well as ICH volumes and edema volumes, and causes of ICH) that might be treatment targets to improve ICH outcomes.

抽象的 脑内出血（ICH）后，血脑屏障（BBB）被破坏 相关的水肿和白细胞从血液渗入组织/血肿。 单核细胞和淋巴细胞进入大脑。 人类的比例与较差的ICH结果有关。 与缺血性卒中相比 和控制权。 因此，生存的重要因素。 和T淋巴细胞作为ICH体积，水肿体积和缺血性病变体积的功能，围绕ICH， 以及ICH的原因。 以及影响血肿的分辨率，复发性出血和复发性严重程度的不同ICH原因 出血将是基于非常强大的初步数据改善生存的分子靶标。 我们提出以下目标。 目的＃1a。 ICH和免疫相关的中性粒细胞，M1单核细胞和特异性T细胞亚群（γδT细胞） M2单核细胞和特定T细胞子群中的修复基因（例如T辅助细胞）在后来表达 遵循ICH（3D，7D）的时代； 目的＃1B。 ICH，这可能与减少的血液T淋巴细胞相关 以后）。 随着时间的流逝，ICH周围的缺血病变 ICH。 与经过修改的波士顿标准23-25所定义的可能与可能的CAA相关的皮质小叶ICH相比。 目的＃3B证明了这一点 ICH的原因，有大量的基因ANES和途径针对每个原因。 人类ICH的分子基础很大程度上没有探索 通过识别与因素相关的分子，将开始增强我们对人类ICH的理解 与ICH结局有关（中性粒细胞，单核细胞，T淋巴细胞以及ICH体积和ICH体积 水肿量和ICH的原因可能是ICH结果的治疗靶标。